Structure and Function Relationship of Crotoxin, a Heterodimeric Neurotoxic Phospholipase A₂ from the Venom of a South-American Rattlesnake

Abstract

Snake neurotoxins that interfere with the release of transmitter at the neuromuscular junction have a clinical and a scientific interest and, therefore, their structure and their mode of action have been extensively studied. Phospholipase A₂ ß-neurotoxins have been found in the venom of Elapidae and Viperidae snakes. They are potent neurotoxins which specifically inhibit the release of acetylcholine from peripheral cholinergic synapses. Although they all possess phospholipase A₂ activity, their quaternary structure is rather heterogeneous. Some of them consist of a single chain phospholipase A₂ polypeptide chain, as ammodytoxin A from the venom of Vipera ammodytes ammodytes (Lee et al, 1984, Ritonja and Gubensek, 1985) or agkistrodotoxin from the venom of Agkistrodon blomhoffii brevicaudus (Chen et al, 1981). Multichain ß-neurotoxins, such as crotoxin, from the venom of Crotalus durissus terrificus, are made of the non covalent association of several subunits homologous to phospholipases A₂, at least one of which possessing enzymatic activity. Finally, ß-bungarotoxins, which are only found in Bungarus venoms, covalently associate a phospholipase A₂ subunit with a non-enzymatic polypeptide homologous to Kunitz-type protease inhibitors (Kondo et al, 1982a; 1982b). The mechanism of action of ß-neurotoxins has been extensively studied in vivo and in vitro. This brief review focusses on crotoxin, the structure-function relationship of which was examined using the complementary approaches of biochemistry, pharmacology, immunochemistry and molecular biology.